The Role Of Neuroinflammation Of The MPFC And VHPC In Development Of Anxiety Associated With Chronic Pain

Chronic pain not only causes unbearable pain in patients but also accompanies with comorbidity,such as anxiety and depression,which seriously affects patients' quality of life.Studies have found that anxiety is closely related to neuroinflammation in the brain,but it is not clear whether the anxiety associated with chronic pain shares a similar mechanism.Therefore,using a neuropathic pain model with selective sciatic nerve injury(spared nerve injury,SNI),we addressed the following questions: 1)In the course of the development of anxiety in SNI rats,whether any changes occur in the amount of microglia cells in the medial prefrontal cortex(mPFC),the ventral hippocampus(vHPC)and the basolateral amygdala(BLA)which are key areas constituting the anxiety neural network;2)Whether there are any changes in the expression of pro-inflammatory factors in these brain regions,such as tumor necrosis factor-alpha(TNF-?);3)Whether minocycline,an inhibitor of microglia,can affect the number of microglia cells and TNF-? expression in these brain regions,and in the same time reverse anxiety-like behaviors of the SNI rats.Our results showed that,at 4 weeks after SNI surgery,the anxiety level of the SNI rats was significantly higher than that of Sham group(p < 0.05).Thus,the SNI rats spent significantly less time both in the central area of open field test and in the open arm of the elevated plus maze.These anxiety-like behaviors lasted beyond 8 weeks after surgery.Using immunohistochemistry analysis,a significantly(p < 0.05)higher density of microglia cells in both the mPFC and vHPC was observed at 2 weeks after SNI surgery and maintained beyond 8 postsurgical weeks.The BLA region showed no such change.In addition,the expression of TNF-? in the mPFC and vHPC was significantly higher at 4 and 8 weeks after surgery in SNI animals,compared with the Sham group.Moreover,sub-chronic treatment with microglia inhibitor minocycline(40mg/kg/day,)for 31 days,started 3 days before nerve injury surgery,significantly alleviated anxiety-like behaviors of the SNI rats when tested at 28 days after surgery(p <0.05).Minocycline also caused reductions of both the density of microglia cells and the expression of TNF-? in the mPFC and vHPC.In summary,our study demonstrated that the anxiety-like behavior in animals with chronic pain is associated with neuroinflammation in key areas of the anxiety neural network.Our finding provides important information for better understanding of the neural mechanism for anxiety disorder associated with chronic pain.Our results may also provide scientific basis for the development of clinical intervention.